rs1060505026

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5

The NM_016277.5(RAB23):c.481G>C(p.Val161Leu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000688 in 1,453,684 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

RAB23
NM_016277.5 missense, splice_region

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 7.08

Publications

2 publications found

Variant links:

Genes affected

RAB23 (HGNC:14263): (RAB23, member RAS oncogene family) This gene encodes a small GTPase of the Ras superfamily. Rab proteins are involved in the regulation of diverse cellular functions associated with intracellular membrane trafficking, including autophagy and immune response to bacterial infection. The encoded protein may play a role in central nervous system development by antagonizing sonic hedgehog signaling. Disruption of this gene has been implicated in Carpenter syndrome as well as cancer. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

RAB23 Gene-Disease associations (from GenCC):

RAB23-related Carpenter syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), ClinGen, G2P
Carpenter syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

RAB23 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 6-57194770-C-G is Pathogenic according to our data. Variant chr6-57194770-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 417740.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAB23	NM_016277.5 link	c.481G>C	p.Val161Leu	missense_variant, splice_region_variant	Exon 5 of 7	ENST00000468148.6	NP_057361.3	Q9ULC3A0A024RD41

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAB23	ENST00000468148.6 link	c.481G>C	p.Val161Leu	missense_variant, splice_region_variant	Exon 5 of 7	1	NM_016277.5	ENSP00000417610.1		Q9ULC3
RAB23	ENST00000317483.4 link	c.481G>C	p.Val161Leu	missense_variant, splice_region_variant	Exon 5 of 7	1		ENSP00000320413.3		Q9ULC3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000401

AC:

AN:

249278

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000887

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.88e-7

AC:

AN:

1453684

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

723554

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33310

American (AMR)

AF:

0.00

AC:

AN:

44510

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26034

East Asian (EAS)

AF:

0.00

AC:

AN:

39492

South Asian (SAS)

AF:

0.00

AC:

AN:

85580

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53334

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5744

European-Non Finnish (NFE)

AF:

9.04e-7

AC:

AN:

1105624

Other (OTH)

AF:

0.00

AC:

AN:

60056

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Carpenter syndrome

Pathogenic:1

Apr 15, 2017

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.89

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Uncertain

0.010

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.47

T;T

Eigen

Benign

0.071

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.96

D;.

M_CAP

Pathogenic

0.59

MetaRNN

Pathogenic

0.85

D;D

MetaSVM

Benign

-0.83

MutationAssessor

Benign

-0.95

N;N

PhyloP100

7.1

PrimateAI

Uncertain

0.70

PROVEAN

Uncertain

-2.7

D;D

REVEL

Uncertain

0.42

Sift

Benign

0.18

T;T

Sift4G

Benign

0.22

T;T

Polyphen

0.030

B;B

Vest4

0.70

MutPred

0.69

Loss of MoRF binding (P = 0.2226);Loss of MoRF binding (P = 0.2226);

MVP

0.78

MPC

0.26

ClinPred

0.48

GERP RS

5.9

Varity_R

0.48

gMVP

0.66

Mutation Taster

=5/95

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

1.0

SpliceAI score (max)

0.87

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.87

Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over